Signal transduction pathways relay information from a variety of different stimuli leading to multiple cellular responses. Consequently, such pathways have attracted a great deal of attention as potential targets for therapeutic intervention. The Mitogen-activated Protein Kinase (MAPK) signaling pathway is one key pathway that transduces a large variety of external signals, leading to cellular responses that include growth, differentiation, inflammation and apoptosis. Accordingly, MAPK is activated by several diverse signals under normal conditions. However, improper regulation of MAPK, including hyperactivity, has been associated with many diseased states. More particularly, improper regulation of the Mitogen-activated Protein Kinase (MAPK) pathway is a distinguishing characteristic in many tumors as well as neurological diseased states such as epilepsy.
p90 Ribosomal S6 Kinase (RSK) is a serine/threonine kinase that is a downstream component of the Mitogen-activated Protein Kinase (MAPK) signaling pathway. Therefore, unregulated stimulation of the MAPK pathway results in unregulated RSK catalytic activity. The contribution of upstream components such as Epidermal Growth Factor Receptor (EGFR) and the products of the proto-oncogenes c-src, ras, and raf to activate the MAPK pathway, resulting in physiological responses by the cell that are associated with diseased states, have been well documented. However, the extent to which these physiological responses function through RSK is unknown.
The paucity of data concerning key biological roles of the Ser/Thr protein kinase RSK family in somatic cells results primarily from the difficulty in distinguishing RSK function from those of MAPK itself and of the many other downstream MAPK effectors. This difficulty has arisen because of the lack of any RSK specific inhibitors. Accordingly, a RSK specific inhibitor is highly desirable for use as a tool for investigating RSK function under normal conditions and under diseased conditions in which regulation of the MAPK signaling pathway has been compromised. One aspect of the present disclosure provides a method for using compositions comprising such inhibitors for the treatment of diseases associated with elevated RSK activity.
Many intracellular pathogens hijacks the host cell's signaling events and trafficking machinery for establishment and maintenance of infection (Kahn, et al., 2002. Trends Biochem Sci 27:308-14). Thus, the host cell signaling events essential for establishing and maintaining infection provide attractive targets for novel anti-infective agents. Accordingly, one set of targets for new anti-infective agents is the signaling events involved in endosomal/phagosomal maturation. For intracellular pathogens to survive in the host cell they must disrupt or avoid the microbicidal machinery. This often involves inhibiting maturation of the endocytotic vesicles and fusion with the lysosomes (See for example, Hackstadt, T. 2000. Traffic 1:93-9 and Scott, et al., 2003. J Membr Biol 193:137-52). Thus, compounds that inhibit the host-cell's signaling events used by the pathogen to impede endosomal/phagosomal maturation would promote fusion of the endocytotic and lysosomal vesicles restoring microbicidal function to the host cell. Applicants have discovered that RSK activity can be inhibited as a means of preventing pathogen disruption of endosomal/phagosomal maturation.
Anti-angiogenic therapy is currently in use to treat multiple pathologies. As disclosed herein, applicants have discovered that RSK activity is required for endothelial cell migration, and accordingly, inhibiting RSK activity represents a novel method for inhibiting angiogenesis. The purpose of the present disclosure is not to overcome shortcomings that have been identified with previous anti-angiogenic treatments. This present disclosure adds to the options for anti-angiogenic treatments and allows for new unique combinations of anti-angiogenic therapeutics.
As disclosed herein applicants have discovered a new set of RSK specific inhibitory compounds that can be used to treat various conditions associated with undesirable RSK activity.